2-(1-(1,3-Thiazolin-2-yl)azetidin-3-yl)thio-carbapenem derivatives

Abstract: Novel 3-Mercapto-1-(1,3-thiazolin-2-yl)azetidine derivatives represented by formula (IX) below or acid addition salts thereof wherein R is hydrogen, C 1 -C 7 alkyl group which is unsubstituted or substituted by hydroxy, C 1 -C 7 alkoxy or C 1 -C 7 alkoxy-C 1 -C 7 alkoxy group; group -COOR 1 (R 1 is hydrogen or C 1 -C 7 alkyl group); or group -CONR 2 R 3 (R 2 and R 3 are, independently each other, hydrogen or C 1 -C 7 alkyl and a process for producing these compounds.

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to novel 3-Mercapto-1-(1,3-thiazolin-2-yl)azetidine derivatives represented by formula (IX) below or acid addition salts thereof wherein R is hydrogen, C 1 -C 7 alkyl group which is unsubstituted or substituted by hydroxy, C 1 -C 7 alkoxy or C 1 -C 7 alkoxy-C 1 -C 7 alkoxy group; group -COOR 1 (R 1 is hydrogen or C 1 -C 7 alkyl group) ; or group -CONR 2 R 3 (R 2 and R 3 are, independently each other, hydrogen or C 1 -C 7 alkyl and a process for producing these compounds. These compounds are useful for the production of carbapenem antibiotics and, more particularly, 1β-methyl-carbapenem derivatives having a methyl group introduced at the 1-position and [1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio group introduced at the 2-position of the carbapenem skeleton. 2. Description of the Prior Art Heretofore, as various antibacterial substances, there have been proposed many carbapenem antibiotic substances having, as a basic skeleton, carba-2-penem-3-carboxylic acid represented by the following formula (A): For example, an initial generation of carbapenem antibiotics is a naturally occurring carbapenem compound such as thienamycin represented by the formula (B): The thienamycin may be obtained from a fermentation broth of Streptomyces cattleya and has a broad range of antibacterial spectra against Gram-positive and Gram-negative bacteria. It has been expected therefore to be developed as a highly useful compound, but its poor chemical stability has precluded its commercialization. With the foregoing background, many researchers have attempted to develop a carbapenem compound having antibacterial activities as high as thienamycin and ensuring more chemical stability. As a result, there has been developed imipenem (INN) represented by the following formula (C): This compound is a practically available antibacterial agent and may be obtained by converting an amino group as a side chain at the 2-position to a formimidoyl group. The imipenem of the formula (C) exhibits antibacterial activities higher than those of the thienamycin and ensures some degree of chemical stability; however, it presents the disadvantage that it is decomposed within a short period of time by kidney dehydropeptidase (DHP) in the living body. For this reason, it cannot be administered singly, and must be used in combination with a DHP inhibitor in order to control its decomposition leading to inactivation. Its formulation for clinical administration is a combination with cilastatin (INN) that is a DHP inhibitor. An antibacterial agent preferred for practical clinical use, however, is one that alone can demonstrate antibacterial activity. Furthermore, the DHP inhibitor to be combined with the antibiotic could exert undesirable actions on tissues of the living body. For these reasons, the combined use should be avoided wherever possible. Thus there has been a growing demand for a carbapenem compound having sufficiently high degrees of both antibacterial activity and resistance to DHP. Recently, there were proposed some carbapenem compounds of the type that could achieve the above objectives. Such carbapenem compounds are 1-methyl-carbapenem compounds in which a methyl group is introduced at the 1-position and various heterocyclyl-thio groups at the 2-position of the carbapenem skeleton. For example, Japanese Laid-Open Patent Publication No. 202,866/1985 to Sankyo discloses 2-heterocyclyl-thio-1-methylcarbapenem compounds including a compound having at the 2-position a (N-methylacetoimidoyl-azetidin-3-yl)thio substituent, represented by the formula (D): It is reported that this compound has superior antibacterial activities as well as a remarkably improved resistance to decomposition by DHP leading to inactivation so that it demonstrates highly useful effects; however, the Japanese Patent document does not provide any specific antibacterial data or working examples. Therefore, Sankyo does not disclose anything about carbapenem compounds having at the 2-position 1-(1,3-thiazolin-2-yl)-azetidin-3-yl-thio substituent according to the present invention. Most recently, International Patent Publication Number WO 93/23,402 to Fujisawa disclosed 2-(3-azetidinylthio) carbapenem compounds represented by the following formula (E): In the specification of this patent publication Fujisawa specifically discloses the carbapenem compounds represented by the following formula (F): wherein R 4 and R 5 are combined together to form optionally substituted imino-containing heterocyclic group: however, among the compounds of formula (F), the only one compound is supported by working example, and there isn't any specific description of antibacterial data whatsoever. No specific compounds according to the present invention are disclosed therein, and any prior patent application mentioned above does not suggest anything about such compounds as having superior pharmacological characteristics as demonstrated and claimed in the present invention. Therefore, there was no anticipation of the specific compounds disclosed and claimed herein. Carbapenem compounds possess a potent antibacterial activity with a broad spectrum. However, like other β-lactam antibacterial agents used in clinical practice, it is anticipated that carbapenem compounds will be uneffective against carbapenem-resistant bacteria. Accordingly, there have been proposed some carbapenem compounds having unique substituents at 2-position of the carbapenem skeleton. Furthermore, even though oral formulations of carbapenem compounds are useful for daily administration, the carbapenem antibiotics which have been proposed in prior patent application are mainly used for injectable formulation. SUMMARY OF THE INVENTION The present invention provides novel 3-Mercapto-1-(1,3-thiazolin-2-yl)azetidine derivatives represented by formula (IX) below or acid addition salts thereof wherein R is hydrogen, C 1 -C 7 alkyl group which is unsubstituted or substituted by hydroxy, C 1 -C 7 alkoxy or C 1 -C 7 alkoxy-C 1 -C 7 alkoxy group; group -COOR 1 (ml is hydrogen or C 1 -C 7 alkyl group); or group -CONR 2 R 3 (R 2 and R 3 are, independently each other, hydrogen or C 1 -C 7 alkyl and a process for producing these compounds. The compounds of the present invention are useful for the production of carbapenem compounds having high antibacterial activities, a strong action of inhibiting β-lactamase as well as improved resistance to kidney dehydropeptidase; more specifically, of carbapenem compounds substituted by a methyl group at the 1-position in the β-configuration, in which particularly a [1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio group is introduced at the 2-position. The compounds of the present invention are particularly useful to provide (1R,5S,6S)-2-[1-(1,3-thiazolin-2-yl)-azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylic acid derivative represented by the following formula: wherein R is hydrogen; lower alkyl group which is unsubstituted or substituted by hydroxy, lower alkoxy or lower alkoxy-lower alkoxy group; group -COOR 1 (R 1 is hydrogen or lower alkyl group); or group -CONR 2 R 3 (R 2 and R 3 are, independently each other, hydrogen or lower alkyl), Y is carboxy, -COO ⊖ or protected carboxy, or a pharmaceutically acceptable salt thereof. More specifically, for the provision of (1R,5S,6S)-2-[1-(1,3-thiazolin-2-yl)azetidin-3-yl]-thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylic acid of the following formula: wherein Y has the same meaning as above, or a pharmaceutically acceptable salt thereof. Still more specifically, the present invention provides (1R,5S,6S)-2-[1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylic acid of the following formula: or a pharmaceutically acceptable salt thereof. The compounds of the present invention are also useful for providing orally administrable carbapenem compounds which are converted into active carbapenem compounds of formula (II) in the body and show potent activities against a number of pathogenic microorganisms. For the above purpose of the invention, (1R,5S,6S)-2-[1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxy late of the following formula: wherein R 4 is ester moiety of an esterified carboxy, or a pharmaceutically acceptable salt thereof, is to be provided. In this respect, a preferable orally administrable carbapenem compound is 1-[(cyclohexyloxy)-carbonyloxy]ethyl (1R,5S,6S)-2-[1-(1,3-thiazolin-2-yl)-azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate of the following formula: or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION In the specification of the present application, the term "lower" qualifying a group of a compound means that the group or compound so qualified has from 1 to 7, preferably from 1 to 4, carbon atoms. The term "alkyl" referred to herein stands for a straight-chained or branched-chain hydrocarbon group having preferably from 1 to 20 carbon atoms and may include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, octyl, isooctyl, monanyl, dodecanyl, pentadecanyl, eicosanyl or the like. The term "alkoxy" referred to herein stands for an alkyl-oxy group in which the "alkyl" group has the meaning as mentioned above. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, n-heptyloxy, isoheptyloxy or the like. Among them, methoxy, ethoxy, isobutoxy, sec-butoxy or tert-butoxy is preferably used. The term "protected carboxy" is esterified carboxy which is represented by the group -COOR 4 (wherein R 4 is ester moiety of an esterified carboxy). Suitable ester moiety of an esterified carboxy represented by the group "R 4 " is lower alkyl which may have at least one suitable substituent(s), and can be represented by the following group: wherein R 5 is hydrogen or alkyl group, R 6 is alkyl or cycloalkyl group in which these groups may be substituted by alkoxy, group: -OP(=O)(OR 7 ) (wherein R 7 is hydrogen, alkyl, aryl or aralkyl), carboxyl or propylglycinamide; and n is 0 or 1. The term "aryl" may be monocyclic or polycyclic aryl group which may have at least one substituent(s) such as alkyl, for example, phenyl, tolyl, xylyl, α-naphthyl or β-naphthyl and the like. Suitable "aralkyl" may include aryl substituted alkyl in which the "aryl" group and "alkyl" group have the meanings as mentioned above. Examples include benzyl, benzhydryl, trityl, phenethyl, α-methylbenzyl, phenylpropyl, naphthylmethyl and the like. The term "cycloalkyl" may be saturated monocyclic hydrocarbon group having from 3 to 7 ring carbon atoms, and for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like. Therefore, suitable "ester moiety" is for example, lower alkanoyloxy(lower)alkyl ester [e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-(or 2-)acetoxyethyl ester, 1-(or 2- or 3-)acetoxypropyl ester, or 1-(or 2- or 3- or 4-)acetoxybutyl ester, 1-(or 2-)propionyloxyethyl ester, 1-(or 2- or 3-)propionyloxypropyl ester, 1-(or 2-)butyryloxyethyl ester, 1-(or 2-)isobutyryloxyethyl ester, 1-(or 2-)pyvaloyloxyethyl ester, 1-(or 2-)hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1-(or 2-)pentanoyloxyethyl ester, etc.], lower alkanesulfonyl(lower)alkyl ester (e.g. 2-mesylethyl ester, etc.), mono(or di or tri)halo(lower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester [e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-butoxycarbonyloxymethyl ester, 1-(or 2-)methoxycarbonyloxyethyl ester, 1-(or 2-)ethoxycarbonyloxyethyl ester, 1-(or 2-)isopropoxycarbonyloxyethyl ester, etc.], cycloalkyloxycarbonyloxy(lower)alkyl ester (e.g. cyclohexyloxycarbonyloxymethyl ester, 1-(or 2-)cyclohexyloxycarbonyloxy ethyl ester, etc.), phthalidylidene(lower)alkyl ester, or (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g. (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; or the like. More preferable example of the protected carboxy thus defined may be pivaloyloxymethyloxycarbonyl or 1-(cyclohexyloxycarbonyl)ethyloxycarbonyl. Typical examples of the compounds of formula (I) are shown in the following Table 1 and Table 2. The pharmaceutically acceptable salts of the above listed compounds are also included in the examples of the compounds. Furthermore, when the compounds of the present invention have an asymmetric carbon in the side chain at the 2-position or 3-position, these optically active compounds can be stereo-selectively obtained by using the optically active starting materials (see the examples described below), or they can be also obtained by resolution of the diastereoisomeric mixture of these compounds by ordinary methods. Therefore, the optically active and stereoisomeric mixture of the compounds (I) should be included in the compounds, The compounds of the formula (I) may be prepared in accordance with the processes as illustrated by the reaction schemes shown below. The compound of formula (I) in which the group "Y" is carboxy or -COO ⊖ may be prepared by the following Reaction Scheme A: wherein L is a leaving group; and R has the same meaning as above. The "leaving group" represented by L in the formula (VI) may, for example, be an azido group; a halogen atom such as chlorine, bromine or fluorine; lower alkanoyloxy group such as acetoxy or propionyloxy; sulfonyloxy group such as benzenesulfonyloxy, tosyloxy or methanesulfonyloxy; lower alkoxy group such as methoxy or ethoxy; lower alkylthio group such as methylthio or ethylthio. The reaction of (1R,5S,6S)-2-[(azetidin-3-yl)]-thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylic acid of formula (V) with the compound of formula (VI) may be carried out, for instance, by reacting the compound of formula (V) with the compound (VI) in an appropriate buffer-solvent of pH 5 to 7 such as a phosphate buffer solution, an acetate buffer solution, a citrate buffer solution, a morpholino-propane sulfonate buffer solution, an N-methylmorpholino phosphate buffer solution or the like. The reaction can be carried out by adding the compound of formula (VI) into the solution mixture of the compound of formula (V) and by stirring the reaction mixture for an appropriate time. The quantity of the compound of formula (VI) is not critical and may vary appropriately in a range from approximately 1 to approximately 10 moles, preferably in a range from approximately 1 to approximately 5 moles, per mole of the compound of formula (V). If necessary, an organic solvent, alcohol such as methanol, ethanol or isopropanol; ether such as diethyl ether or tetrahydrofuran; acetonitrile; dimethylformamide; or dimethylacetamide can be used as the reaction solvent together with the above buffer solution. The reaction temperature is not limited to a particular range and many vary in a wide range according to the starting material of (VI) to be used. It may range generally from about -78°C to about 50°C, preferably from about -20°C to about 0°C. The reaction may be finished in approximately 5 minutes to approximately 5 hours. The compounds of formula (V) to be employed as a starting compound in the above reaction are known compounds or may be prepared in accordance with the known method described in Japanese Patent Publication No. 255,280/1988. Furthermore, the compound of the formula (I) in which the group "Y'" is carboxy or -COO ⊖ may also be prepared in accordance with the following Reaction Scheme B. wherein R a is an acyl group; R' is a carboxyl protecting group; and R has the same meaning as above. The term "acyl group" represented by R a may be, in a narrower sense, a moiety obtainable by removing the hydroxyl group from the carboxyl group of an organic carboxylic acid as well as, in a broader sense, any acyl group derived from an organic sulfonic acid or an organic phosphoric acid. Such an acyl group may include, for example, a lower alkanoyl group such as acetyl, propionyl, butyryl or the like, a (halo)lower alkyl sulfonyl group such as methanesulfonyl, trifluoromethanesulfonyl or the like; a substituted or unsubstituted arylsulfonyl group such as benzenesulfonyl, p-nitrobenzenesulfonyl, p-bromo-benzenesulfonyl, toluenesulfonyl, 2,4,6-triisopropylbenzenesulfonyl or the like; and diphenylphosphoryl. The term "carboxyl protecting group" represented by R' stands for any group capable of protecting the carboxyl group of the compound involved without adversely affecting any other substituents and the reactions that follow and may include, for example, an ester residue such as a lower alkyl ester residue including, for example, methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-, iso-, sec- or tert.-butyl ester, n-hexyl ester or the like; an aralkyl ester residue including, for example, benzyl ester, n-nitrobenzyl ester, o-nitrobenzyl ester, p-methoxybenzyl ester or the like; and a lower aliphatic acyloxymethyl ester residue including, for example, acetoxymethyl ester, propionyloxymethyl ester, n- or iso-butyryloxymethyl ester, pivaloxyloxymethyl ester or the like. The reaction of the compound of formula (VIII) with [1-(1,3-thiazolin-2-yl)azetidin-3-yl]thiol of the formula (IX) may be carried out, for instance, by reacting the compound of formula (VIII) with the compound of formula (IX) in an amount ranging from approximately 0.5 molar to approximately 5 molar, preferably from approximately 0.8 molar to approximately 3 molar amount in an appropriate solvent such as tetrahydrofuran, dichloromethane, dioxane, dimethylformamide, dimethylsulfoxide; acetonitrile, hexamethylene phosphoramide or the like, preferable in the presence of a base such as sodium hydrogen carbonate, potassium carbonate, triethylamine, diisopropylethyl amine or the like at a temperature ranging from approximately -40°C to approximately 25°C for approximately 30 minutes to approximately 24 hours. Preferably, the reaction may be carried out in an inert atmosphere, for example in an atmosphere of nitrogen gas or argon gas. The reaction described above provides the compound of formula (X), and the resulting reaction mixture containing the compound of formula (X) may be used for the next reaction without further purification; or the compound (X) may be isolated from the reaction mixture by ordinary methods, if necessary. In the reaction of the compound of formula (VIII) with the compound of formula (IX), another compound (IX') wherein the mercapto group of the formula (IX) is protected by a merecapto-protecting group may be used instead of the compound (IX). The reaction may be carried out in the following manner: the mercapto-protecting group of the compound (IX') is removed by ordinary methods used in the amino acid chemistry, then, without isolating the resulting compound (IX), to the reaction mixture the compound of formula (VIII) is added. The reaction condition is the same as above. The carbapenem compounds of the formula (VII) may be obtained by removal of the carboxyl protecting group R' of the compounds of the formula (X) obtained by the reaction method described above. The removal of the protecting group R' may be made by a reaction known per se for removing a protective group, such as solvolysis or hydrogenolysis. In a typical reaction, the compound represented by formula (X) may be treated, for instance, in a mixture of solvents such as tetrahydrofuran-water, tetrahydrofuran-ethanol-water, dioxane-water, dioxane-ethanol-water, n-butanol-water or the like containing a acetate buffer solution (pH 5.5), morpholino-propane sulfonic acid-sodium hydroxide buffer solution (pH 5.5), a phosphate buffer solution (pH 5.5), dipotassium phosphate, sodium bicarbonate or the like, using hydrogen under 1 to 4 atmospheric pressures, in the presence of a catalyst for hydrogenation such as platinum oxide, palladium-activated carbon or palladium hydroxide-activated carbon at temperatures ranging from approximately 0°C to approximately 50°C for approximately 0.25 to approximately 5 hours. Furthermore, the removal of the protecting group R' of the compound of formula (X) may also be carried out by reacting the compound (X) with zinc in a buffer. In a typical reaction, the compound of formula (X) may be treated with zinc in an appropriate buffer solvent of pH 5 to 7 such as a phosphate buffer solution, an acetate buffer solution, a citrate buffer solution, a morphorinopropanesulfonate buffer solution, or an N-methylmorphorine buffer solution. Zinc used in the reaction may include, for example, elemental zinc in the form of powder, flower or granule or the like. The amount of zinc used in this reaction is not strictly limited; however, in general, it is conveniently about 1 to 10 parts by weight, preferably 1 to 5 parts by weight per part by weight of the compound of formula (X) to be reacted. In this reaction, an organic solvent may be used in combination. Examples of the solvent are alcohols such as ethanol, propanol and n-butanol; ethers such as diethyl ether and tetrahydrofuran; acetonitrile, dimethylformamide and dimethylacetamide. Usually, the reaction may be finished in approximately 5 minutes to approximately 5 hours in a reaction temperature from about -20°C to about 50°C, preferably from the room temperature to about 30°C. The compound of formula (VIII) to be employed as a starting compound in the above reaction is known per se and may be prepared in such a manner as disclosed, for example, in Japanese Laid-Open Patent Publication No. 123,985/1981 or, more preferably, in accordance with the stereo-selectivity method as disclosed in Japanese Laid-Open Patent Publication No. 284,176/1988. Furthermore, [1-(1,3-thiazolin-2-yl)azetidin-3-yl]thiol of the formula (IX) may be prepared in accordance with the method described in the synthetic examples or working examples mentioned later, or may be easily prepared from commercially available compounds. As a result, (1R,5S,6S)-2-[1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acids represented by formula (I) in which "Y" is carboxy are produced in extremely high yield. These compounds may be isolated by using ion-exchange resins or polymer resins. The ester derivatives of the formula (I) may be prepared in accordance with the following Reaction Scheme C: wherein X is halogen; and R, R 5 , R 6 and n have the same meanings as above. In the Reaction Scheme C, halogen represented by X may be chlorine, iodine, bromine or fluorine. The reaction of (1R,5S,6S)-[1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid of formula (VII) with the compound of formula (XI) may be carried out, for instance, first by obtaining an alkali metal salt of formula (VII) in water by reacting the compound of formula (VII) with an appropriate alkali metal bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or the like. Then, the alkali metal salt of formula (VII) thus obtained is reacted with the compound of formula (XI) in inert organic solvent, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane; carbon hydrides such as benzene, toluene, xylene, cyclohexane; N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, preferably in dimethylformamide under stirring. The quantity of the alkali metal base is not critical and may vary appropriately in a range from approximately 1 to approximately 10 moles, preferably in a range from approximately 1 to approximately 5 moles, per mole of the compound (VII). The reaction temperature is not limited to a particular range and may vary from about 0°C to room temperature. The reaction may be finished in approximately 2 or 3 minutes to approximately 1 hour under these conditions. Furthermore, the quantity of the compound of formula (XI) is not critical and may vary appropriately in a range from approximately 1 to approximately 3 moles, preferably in a range from approximately 1 mole to approximately 1.5 moles, per mole of the alkali metal salt of formula (VII). The reaction temperature is not limited and generally may vary in a range from about -20°C to about 50°C, preferably in a range from 0°C to room temperature, and the reaction may be finished in approximately 10 minutes to approximately 2-3 hours. Thus, (1R,5S,6S)-2-[1-(1,3-thiazolin-2-yl)-azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylates represented by the formula (I) in which Y is protected carboxy [compounds of formula (XII)] are produced and these compounds may be isolated and purified by usual method, for example, filtration, decantation, extraction, washing, removal of the solvent, column chromatography, thin-layer chromatography, re-crystalization, distillation, sublimation or the like. The compounds of formula (VII) to be employed as a starting compound in the above Reaction Scheme C can be prepared in accordance with the method described in the examples mentioned later. The compounds represented by formula (I) may be converted to a pharmaceutically acceptable acid addition salt thereof with inorganic or organic acids; these include, for example, aliphatic acid such as acetic acid, propionic acid, butyric acid, trifluoroacetic acid, trichloroacetic acid or the like; substituted or unsubstituted benzoic acid such as benzoic acid, p-nitrobenzoic acid or the like; lower-(halo)alkylsulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid or the like; substituted or unsubstituted arylsulfonic acid such as benzensulfonic acid, p-nitro benzenesulfonic acid, p-bromobenzenesulfonic acid, toluenesulfonic acid, 2,4,6-triisopropylbenzensulfonic acid or the like; organic phosphinic acid such as diphenylphosphinic acid; and inorganic acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, hydriodic acid, borofluoric acid, nitrous acid or the like. The compounds of formula (I) are compounds that are extremely stable against dehydropeptidase (DHP) known as a kidney enzyme and have superior antibacterial activities. Furthermore, the orally administrable carbapenem compounds show good intestinal absorption in the body and easily converted to active carbapenem compound which is highly active against a number of pathogenic microorganisms. Therefore, the carbapenem compounds of formula (I) in which the group Y is protective carboxy may be used as pro-drug type antibiotics for oral administration and are useful for practical clinical use. The remarkably high antibacterial activities, intestinal absorption and stability against the kidney DHP of the compounds of formula (I) have been determined by biological tests (cf. EP 0 632 039 Al). The invention features the following embodiments: 1. 3-Mercapto-1-(1,3-thiazolin-2-yl)azetidine derivatives represented by formula (IX) below or acid addition salts thereof wherein R is hydrogen; C 1 -C 7 alkyl group which is unsubstituted or substituted by hydroxy, C 1 -C 7 alkoxy or C 1 -C 7 alkoxy-C 1 -C 7 alkoxy group; group -COOR 1 (R 1 is hydrogen or C 1 -C 7 alkyl group); or group -CONR 2 R 3 (R 2 and R 3 are, independently each other, hydrogen or C 1 -C 7 alkyl). 2. The compound of item 1 which is 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine of the following formula: or acid addition salt thereof. 3. The compound of item 1 which is 3-mercapto-1-(4-methoxymethoxymethyl-1,3-thiazolin-2-yl)azetidine of the following formula: or acid addition salt thereof. 4. A process for manufacturing the compound represented by formula (IX) of item 1 or an acid addition salt thereof, which process is characterized in that the acetyl group is cleaved off from 3-acetylthio-1-(1,3-thiazolin-2-yl)azetidine derivative represented by formula (XIII) below or an acid addition salt thereof wherein R has the same meaning as defined in claim 1. 5. The process of item 4 wherein R is hydrogen. 6. The process of item 4 wherein R is methoxymethoxymethyl. 7. A process for manufacturing the compound represented by formula (IX) of item 1 or an acid addition salt thereof, which process is characterized in that (a) 3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine derivative represented by formula (XIV) below wherein R has the same meaning as defined in claim 1 is made to react with di(lower)alkylazodicaroboxylate, triphenylphosphine and thioacetic acid, and that (b) the acetyl group is cleaved off from the resulting 3-acetylthio-1-(1,3-thiazolin-2-yl)azetidine derivative represented by formula (XIII) below or an acid addition salt thereof wherein R has the same meaning as defined in item 1. 8. The process of item 7 wherein R is hydrogen. 9. The process of item 7 wherein R is methoxymethoxymethyl. 10. 3-Acetylthio-1-(1,3-thiazolin-2-yl)azetidine derivative represented by formula (XIII) below or an acid addition salt thereof wherein R has the same meaning as defined in item 1. 11. The compound of item 10 which is 3-acetylthio-1-(1,3-thiazolin-2-yl)azetidine of the following formula or an acid addition salt thereof. 12. The compound of item 10 which is 3-acetylthio-1-(4-methoxymethoxymethyl-1,3-thiazolin-2-yl)azetidine of the following formula: or an acid addition salt thereof. 13. 3-Hydroxy-1-(1,3-thiazolin-2-yl)azetidine derivative represented by formula (XIV) below or an acid addition salt thereof wherein R has the same meaning as defined in item 1. 14. The compound of item 13 which is 3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine of the following formula or an acid addition salt thereof. 15. The compound of item 10 which is 3-hydroxy-1-(4-methoxymethoxymethyl-1,3-thiazolin-2-yl)azetidine of the following formula: or an acid addition salt thereof. 16. A process for manufacturing the compound represented by formula (XIV) of item 13 or an acid addition salt thereof, which process is characterized in that 3-hydroxyazetidine represented by formula (XV) below is made to react with 2-methylthio-1,3-thiazolidine derivative by formula (XVI) below wherein R has the same meaning as defined in item 1. 17. The process of item 7 wherein R is hydrogen. 18. The process of item 7 wherein R is methoxymethoxymethyl. The production of the carbapenem compounds of the formula (I) will be described more in detail by way of working examples. In this context, preparation 1 and 2 described below relate to the subject-matter claimed, whereas the further preparations and examples are illustratively given with regard to the uses of the claimed compounds. In the following description, the following symbols are used to have the particular meanings. Me : methyl group Et : ethyl group Ac : acetyl group Ph : phenyl group PNB : p-nitrobenzyl group PNZ : p-nitrobenzyloxycarbonyl group i-Pr : isopropyl t-But : tert.-butyl Boc : t-butoxycarbonyl Preparation 1: (a) To a solution of 109 mg of 3-hydroxyazetidine.HCl [Compound (1)] in 5 ml of ethanol was added a mixture of 133 mg of 2-methylthiazoline [Compound (2)] and sodium methoxide, and the reaction mixture was refluxed for 8 hours. After removal of the solvent under reduced pressure, the resulting residue was dissolved in chloroform and washed with 50 % aqueous potassium carbonate solution. The solvent was removed under reduced pressure to give 119 mg (81.5 %) of 3-hydroxy-1-(thiazolin-2-yl)azetidine [Compound (3)] as a crystaline. 1 H-NMR (CDCl 3 ) δ : 3.356 (t, 2H, J = 7.26Hz), 3.70∼4.00 (m, 4H), 4.211 (t, 2H, J = 8.21 Hz), 4.622∼4.705 (m, 1H), 4.971 (s, 1H) (b) To a mixture solution of triphenylphosphine and diethyl azodicarboxylate in 10 ml of tetrahydrofuran was added a mixture of 119 mg of Compound (3) and thioacetic acid under ice-cooling, and the reaction mixture was stirred for 1 hour at the same condition, then for 1 hour at room temperature. After the reaction solvent was removed under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform : ethanol = 1 : 1) to give 107 mg (65 %) of 3-acetylthio-1-(thiazolin-2-yl)azetidine [Compound (4)]. 1 H-NMR (CDCl 3 ) δ : 2.333 (s, 3H), 3.352 (t, 2H, J = 7.26 Hz), 3.885 (dd, 2H, J = 8.24, 5.28 Hz), 4.012 (t, 2H, J = 7.26 Hz), 4.250∼4.374 (m, 1H), 4.426 (t, 2H, J = 8.25 Hz) Preparation 2: (a) To a mixture solution of 4.88 g of 4(R)-hydroxymethyl-2-mercapto-1,3-thiazoline [Compound (5)] and 22.8 ml of diisopropylethylamine in 65 ml of dry methanol was added 14.00 g of methyl iodide under refluxing condition, and the reaction mixture was refluxed for 1 hour. After removal of the solvent under reduced pressure, the resulting residue was dissolved in ethyl acetate and the organic layer was washed with saturated sodium bicarbonate solution, water and saturated saline solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform-acetone) to give 3.14 g (59 %) of 4(R)-hydroxymethyl-2-methylthio-1,3-thiazoline [Compound (6)]. 1 H-NMR (CDCl 3 ) δ : 2.53 (s, 3H) , 3.30 (dd, 1H, J = 8.6, 10.6 Hz), 3.44 (dd, 1H, J = 7.6, 10.6 Hz), 3.67-3.73 (m, 1H), 3.86-3.92 (m, 1H), 4.51-4.68 (m, 1H) (b) 3.14 g of Compound (6) obtained in the step (a) and 6.7 ml of diisopropylethylamine were dissolved in 40 ml of dry dichloromethane solution. 2.33 g of chloromethylmethyl ether was added to the above mixture under ice-cooling and the reaction mixture was stirred for 1 hour under the same condition and for 15 hours at room temperature. After the reaction, the reaction mixture was washed with water, saturated sodium bicarbonate solution and saturated saline solution, and dried over magnesium sulfate. After removal of the solvent, the resulting residue was purified by silica gel column chromatography (chloroform-ethyl acetate) to give 1.42 g (36 %) of 4(R)-methoxy-methyloxymethyl-2-methylthio-1,3-thiazoline [Compound (7)]. 1 H-NMR (CDCl 3 ) δ : 2.55 (s, 3H), 3.35 (dd, 1H, J = 7.3, 10.9Hz), 3.38 (s, 3H), 3.42 (dd, 1H, J=8.3, 10.9 Hz), 3.474 (dd, 1H, J=7.6, 9.9 Hz) 3.78 (dd, 1H, J = 5.0, 9.9 Hz), 4.66-4.7 0 (m, 1H), 4.67 (s, 2 H) (c) A mixture solution of 0.924 g of Compound (7) obtained in the above step (b), 0.540 g of 3-hydroxyazetidine.HCl [Compound (1)], 0.490 g of sodium bicarbonate and 0.160 g of acetic acid in 20 ml of ethanol was refluxed for 24 hours. After removal of the solvent, the resulting residue was dissolved in chloroform and washed with 50 % potassium carbonate aqueous solution. The organic layer was dried over magnesium sulfate and then removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (10 % methanol in chloroform) to give 0.590 g (57 %) of 1-(4(R)-methoxymethyloxymethyl-1,3-thiazolin-2-yl)-3-hydroxyazetidine [Compound (8)]. 1 H-NMR (CDCl 3 ) δ : 3.25-3.32 (m, 1H), 3.37 (s, 3H), 3.40-3.46 (m, 1H), 3.47-3.52 (m, 1H), 3.63 (dd, 1H, J = 5.3, 9.9 Hz), 3.79-3.89 (m, 2H), 4.16-4.22 (m, 2H), 4.38-4.45 (m, 1H), 4.61-4.68 (m, 3H) (d) To a solution of 1.40 g of triphenylphosphine in 15 ml of dry tetrahydrofuran was added 0.800 ml of diethyl azodicarboxylate under ice-cooling and the mixture solution was stirred for 0.5 hour. Then, a mixture solution of 0.588 g of Compound (8) obtained in the above step (c) and 0.361 ml of thioacetic acid in 15 ml of dry tetrahydrofuran was added dropwise to the above solution under ice-cooling and the reaction mixture was stirred for 1 hour under the same condition and for 1 hour at room temperature. After removal of the solvent, the resulting residue was purified by silica gel column chromatography (chloroform-acetone) to give 0.600 g (82 %) of 2-acetyl-thio-1-(4(R)-methoxymethyloxymethyl-1,3-thiazolin-2-yl)azetidine [Compound (9)]. 1 H-NMR (CDCl 3 ) δ : 2.33 (s, 3H), 3.29 (dd, 1H , J = 6.3, 10.9 Hz), 3.37 (s, 3H), 3.43 (dd, 1H, J = 7.6, 10.9 Hz), 3.50 (dd, 1H, J = 7.9, 9.9 Hz), 3.67 (dd, 1H, J = 4.6, 9.9 Hz), 3.86-3.91 (m, 2H), 4.25-4.34 (m, 1H), 4.39-4.51 (m, 3H), 4.66 (s, 2H) Preparation 3: (a) 0.3 g of sodium hydroxide was added to 64.8 g of benzylalcohol and the reaction mixture was cooled to 0°C. To this reaction mixture was added 12.9 g of β-butyrolactone and the mixture was stirred for 5 minutes at 0°C and for 2 hours at room temperature. After reaction, the reaction solution was neutralized by adding 15 ml of 1N-HCl solution and the separated organic layer was washed with saturated sodium bicarbonate aqueous solution and saline, and dried over magnesium sulfate. The resulting organic layer was distilled under reduced pressure to give 23.3 g (79 %) of benzyl 3-hydroxybutanoate [Compound (11)] as oil. Boiling point : 134°C/8 mmHg 1 H-NMR (CDCl 3 ) δ : 1.22 (d, 3 H, J = 6.3 Hz), 2.41∼2.58 (m, 2H), 2.95 (brs, 1H), 4.15∼4.24 (m, 1H), 5.14 (s, 2H), 7.30∼7.36 (m, 5H) (b) A mixture solution of 1.0 g of benzyl 3-hydroxybutanoate obtained in the step (a), 1.0 ml of triethylamine and 63 mg of 4-dimethylaminopyridine in 10 ml of methylene chloride was cooled to 0°C. To this solution was added 1.79 g of diphenyl phosphorochloridate under nitrogen atmosphere and the reaction mixture was stirred for 3 hours at room temperature. After reaction, the reaction mixture was washed with 1N-HCl solution, saturated sodium bicarbonate aqueous solution and saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography with methylene chloride to give 1.85 g (84 %) of 3-diphenoxyphosphoryloxybutanoate [Compound (12)] as colorless oil. 1 H-NMR (CDCl 3 ) δ : 1.32 (d, 3H, J = 6.3Hz), 2.52 (dd, 1H, J = 6.3 Hz, 15.8Hz), 2.72 (dd, 1H, J = 6.3Hz, 15.8Hz), 4.92 (d, 1H, J = 12.9Hz), 4.98 (d, 1H, J = 12.9Hz), 4.9∼5.1 (m, 1H), 7.06∼7.20 (m, 15H) (c) To a solution of 1.23 g of Compound (12) obtained in the step (b), 8 ml of ethyl acetate and 8 ml of ethanol was added 61 mg of 10 % palladium-carbon, and the reaction mixture was stirred for 1 hour under H 2 gas atmosphere at room temperature, Then, palladium-carbon was filtrated off and the organic layer was removed under reduced pressure. The resulting residue was dissolved in 8 ml of methylene chloride and to this solution was added a mixture of 847 mg of sodium bicarbonate, 8 ml of water, 98 ml of tetrabutylammonium phosphate and 570 mg of chloromethyl chlorosulfonate, and the reaction mixture was stirred for 2 hours at room temperature. After reaction, the organic layer was separated and washed with saline and dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography with methylene chloride to give 1.10 g (99 %) of chloromethyl 3-diphenylphosphoryloxybutanoate [Compound (13)] as colorless oil. 1 H-NMR (CDCl 3 ) δ : 1.46 (d, 3H, J = 6.3Hz), 2.66 (dd, 1H, J = 6.3Hz, 15.8Hz), 2.85 (dd, 1H, J = 6.3Hz, 15.8Hz), 5.09∼5.18 (m, 1H), 5.58 (d, 1H, J = 6.0Hz), 5.61 (d, 1H, J=6.0Hz), 7.16∼7.37 (m, 10H) Preparation 4: (a) To a solution of 12.0 g of ε-hexanolactone in 20 ml of ethanol was added a solution of 11.7 g of potassium hydroxide in 20 ml of water under ice-cooling and the reaction mixture was stirred for 2.5 hours at 40°C. After reaction, the reaction mixture was adjusted to pH 9 by adding 1N-HCl solution and washed with ethyl acetate (twice). The aqueous layer was concentrated under reduced pressure and the residue was adjusted to pH 1 by adding 1N-HCl solution and extracted by ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure to give 11.5 g of 6-hydroxyhexanoic acid. A mixture of 1 g of 6-hydroxyhexanoic acid obtained above, 0.72 mg of sodium bicarbonate in 20 ml of water was stirred for 15 minutes. After reaction, the solvent was removed and the resulting residue was washed with acetonitrile to give 1.24 g of sodium 6-hydroxyhexanoic acid. Then, 276 mg of this compound was dissolved in 2.7 ml of dimethylformamide and to this solution was added 161 mg of methoxymethyl chloride and the reaction mixture was stirred for 1.5 hours at room temperature. After adding 10 ml of ethyl acetate to the reaction mixture, the organic layer was washed with saline, saturated sodium bicarbonate aqueous solution and saline respectively and dried over magnesium sulfate. The solvent was removed to give 190 mg (59 %) of methoxymethyl 6-hydroxyhexanoate [Compound (15)]. 1 H-NMR (CDCl 3 ) δ : 1.36∼1.72 (m, 6H), 2.34 (t, 2H, J = 7.2Hz), 3.45 (s, 3H), 4.07 (t, 2H, J = 6.7Hz), 5.16 (s, 2H), 5.19 (s, 2H), 5.22 (s, 2H), 7.53 (d, 4H, J = 8.7Hz), 8.23 (d, 4H, J = 8.7Hz) (b) To a solution of 25 g of phosphorus trichloride in 70 ml of diethyl ether was added dropwise during 30 minutes a mixture of 51 ml of diisopropylamine and 60 ml of diethyl ether at -10°C, then the reaction mixture was stirred for 1 hour at room temperature. After reaction, unsolved substance was filtrated off and the filtrate was distilled under reduced pressure to give 19.8 g (53 %) of phosphorus diisopropylamino dichloride as oil. b.p. 57°C/4 mmHg. To a solution of 2.06 g of phosphorus diisopropylamino dichloride in 40 ml of methylene chloride was added 4.19 ml of diisopropylamine at -30°C under nitrogen atmosphere and 3.06 g of p-nitrobenzylalcohol was added. The reaction mixture was stirred for 0.5 hour at the same temperature and further 0.5 hour at room temperature. After removal of the solvent, the resulting residue was dissolved in 40 ml of diethyl ether and washed with saturated saline solution and dried over magnesium sulfate. The solvent was removed to give 4.50 g (100 %) of diisopropylamino-di-p-nitrobenzylphosphite [Compound (16)] as yellowish solid. 1 H-NMR (CDCl 3 ) δ : 1.23 (d, 12H, J = 6.6 Hz), 3.71 (q, 1H, J = 6.6 Hz), 3.73 (q, 1H, J = 6.6 Hz), 4.75∼4.91 (m, 4H), 7.51 (d, 4H, J = 8.2Hz), 8.21 (d, 4H, J = 8.2 Hz) (c) A mixture solution of 100 mg of Compound (15) obtained in the step (a), 87.4 mg of tetrazole and 274 mg of Compound (16) obtained in the step (b) in 10 ml of methylene chloride was stirred for 1.5 hour at room temperature. Then, the reaction mixture was cooled to -40°C and 215 mg of 3-chloroperbenzoic acid was added to the reaction mixture and the reaction mixture was stirred for 30 minutes. After reaction, the mixture was washed with saturated saline solution, 10 % sodium thiosulfate aqueous solution, saturated sodium bicarbonate aqueous solution and saturated saline solution respectively. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure to give 306 mg (95 %) of methoxymethyl 6-di-p-nitrobenzyloxy phosphoryloxyhexanoate [Compound (17)]. 1 H-NMR (CDCl 3 ) δ : 1.36∼1.72 (m, 6H), 2.34 (t, 2H, J = 7.2 Hz), 3.45 (s, 3H), 4.07 (t, 2H, J = 6.8Hz), 5.16 (s, 2H), 5.19 (s, 2H), 5.22 (s, 2H), 7.53 (d, 4H, J = 8.7Hz), 8.23 (d, 4H, J = 8.7Hz) (d) To a solution of 206 mg of Compound (17) obtained in the step (c) above in 2 ml of tetrahydrofuran was added 1 ml of 4N-HCl solution and the reaction mixture was stirred for 1.5 hour at room temperature. After reaction, the reaction mixture was adjusted to pH 1 by adding 1N-NaOH solution and washed with diethyl ether. Then, the water layer was adjusted to pH 1 by adding 1N-HCl solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was removed to give 96 mg (51 %) of 6-di-p-nitrobenzyloxy-phosphoryloxyhexanoic acid. Then, 96 mg of this hexanoic acid was dissolved in 4.8 ml of methylene chloride and to this solution was added a mixture solution of 51.3 mg of sodium bicarbonate in 4.8 ml of water, 6.6 mg of tetrabutylammonium hydrogen sulfate and 40.4 mg of chloromethyl chlorosulfonate, and the reaction mixture was stirred for 1 hour at room temperature. After reaction, the organic layer was separated and washed with saturated sodium bicarbonate aqueous solution and saline, and dried over magnesium sulfate. After removal of the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (methylene chloride-acetone) to give 69 mg (55 %) of chloromethyl 6-di-p-nitrobenzyloxyphosphoryloxyhexanoate [Compound (18)]. 1 H-NMR (CDCl 3 ) δ : 1.37∼1.71 (m, 6H) , 2.37 (t, 2H, J = 7.2Hz), 4.07 (t, 2H, J = 6.6Hz), 5.16 (s, 2H), 5.19 (s, 2H), 5.69 (s, 2H), 7.54 (d , 4H, J = 8.5Hz), 8.23 (d, 4H, J = 8.5Hz) Preparation 5: To a solution of 10 g of azelaic acid in 200 ml of acetonitrile were added 16.2 mg of triethylamine and 11.4 g of p-nitrobenzylbromide at nitrogen atmosphere under ice-cooling and the reaction mixture was stirred for 3 hours. After reaction, the reaction mixture was concentrated and 100 ml of water was added. The solution was adjusted to pH 2 by adding 1N-HCl solution and extracted 50 ml of ethyl acetate (twice). The organic layer was washed with saturated saline solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (methylene chloridemethanol) to give 4.51 g (26 %) of mono-p-nitrobenzylazelate. Then, to a solution of 550 mg of this azelate in 10 ml of methylene chloride were added 428 mg of sodium bicarbonate in 10 ml of water. 57 mg of tetrabutylammonium hydrogen sulfate and 336 mg of chloromethyl chlorosulfonate, and the reaction mixture was stirred vigorously for 2 hours at room temperature. After reaction, the reaction mixture was washed with saturated sodium bicarbonate aqueous solution and saturated saline solution, and dried over magnesium sulfate. After removal of the solvent, the resulting residue was purified by silica gel column chromatography (methylene chloride) to give 450 mg (74 %) of p-nitrobenzyl chloromethylazelate [Compound (20)]. 1 H-NMR (CDCl 3 ) δ : 1.20∼1.40 (m, 10H), 2.37 (t, 2H, J = 7.3Hz), 2.39 (t, 2H, J = 7.2Hz), 5.20 (s, 2H), 5.70 (s, 2H), 7.51 (d, 2H, J = 8.7Hz), 8.23 (d, 2H, J = 8.7Hz) Preparation 6: (a) A mixture solution of 5.0 g of L-proline, 9.91 g of p-toluenesulfonic acid monohydrate and 6.65 g of p-nitrobenzyl alcohol in 100 ml of benzene was refluxed for 2 days by using Dean-Stark trap. After reaction, the solvent was removed under reduced pressure and the resulting residue was washed with diethyl ether to give 21.7 g of L-proline p-nitrobenzyl ester p-toluenesulfonic acid salt as oil. Then, a mixture solution of 12.17 g of Boc-glycine and 13.32 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.hydrochloride in 150 ml of ethylene chloride was stirred for 25 minutes under ice-cooling at nitrogen atmosphere. To this reaction mixture was added a solution of 29.36 g of the compound obtained above in 100 ml ethylene chloride and the reaction mixture was stirred overnight at room temperature. After reaction, the reaction mixture was washed with 10 % citric acid aqueous solution, 4 % sodium bicarbonate aqueous solution and saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give 8.00 g of [N-(t-butoxycarbonyl)glycyl]L-proline p-nitrobenzyl ester [Compound (22)]. 1 H-NMR (CDCl 3 ) δ : 1.45 (s, 9H), 1.96∼2.33 (m, 4H), 3.43∼3.70 (m, 2H), 3.93∼4.01 (m, 2H), 4.59 (dd, 1H, J = 4.0 Hz, 8.6 Hz), 5.23 (d, 1H, J = 13.5Hz), 5.30 (d, 1H, J = 13.5Hz), 5.37 (br, 1H), 7.52 (d, 2H, J = 8.9Hz), 8.23 (d, 2H, J = 8.9Hz) (b) To a solution of 4.10 g of Compound (22) obtained in the step (a) in 5 ml of methylene chloride was added 2.5 ml of trifluoroacetic acid under ice-cooling and the reaction mixture was stirred for 1 hour, then, 4 ml of trifluoroacetic acid was added to the reaction mixture and the stirring was continued for 2 hours. After reaction, the solvent was removed to give 5.82 g of glycyl-L-proline p-nitrobenzyl ester trifluoroacetic acid salt as pale brownish oil. Then, to an ice-cooled solution of 5.54 g of the compound obtained above and 1.499 g of glutaric anhydride in 50 ml of methylene chloride was added 1.83 ml of triethylamine, and the reaction mixture was stirred for 20 minutes at the same temperature. After reaction, 60 ml of 10 % citric acid aqueous solution and 200 ml of ethyl acetate were added to the reaction mixture and the organic layer was separated. The organic layer was extracted with 300 ml of 4 % sodium bicarbonate aqueous solution, and the extraction was adjusted to pH 4 and extracted with ethyl acetate. The organic solvent was removed under reduced pressure to give 3.43 g of [N-(4-carboxybutanoyl)glycyl]-L-prolin p-nitrobenzyl ester [Compound (23)] as pale yellowish oil. 1 H-NMR (CDCl 3 ) δ : 1.90∼2.20 (m, 3H), 1.97 (quintet, 2H, J = 7.3Hz), 2.20∼2.34 (m, 1H), 2.41 (t, 2H, J = 7.3Hz), 2.44 (t, 2H, J = 7.3Hz), 3.53∼3.75 (m, 2H), 4. 04 (dd, 1H, J = 4.3Hz, 17.5Hz), 4.22 (dd, 1H, J = 4.9Hz, 17.5Hz), 4.58 (dd, 1H, J = 4.0Hz, 8.9Hz), 5.20 (d, 1H, J = 13.5Hz), 5.32 (d, 1H, J = 13.5Hz), 6.85 (br, 1H), 7.50 (d, 2H, J = 8.6Hz), 8.22 (d, 2H, J = 8.6Hz) (c) To a solution of 3.09 g of Compound (23) obtained in the step (b) in 70 ml of methylene chloride were added 1.85 g of sodium bicarbonate in 70 ml of water, 249 mg of tetrabutylammonium hydrogen sulfate and 1.57 g of ClCH 2 SO 3 Cl, and the reaction mixture was stirred for 140 minutes at room temperature. After reaction, the organic layer was separated and washed with 4 % sodium bicarbonate aqueous solution and saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 3.00 g of [N-(4-chloromethyloxycarbonylbutanoyl)glycyl]-L-proline p-nitrobenzyl ester as pale yellowish oil. Then, a mixture solution of 2.86 g of the compound obtained above and 1.83 g of sodium iodide in 20 ml of acetonitrile was refluxed for 2 hours. After reaction, the solvent was removed and the resulting residue was dissolved in 70 ml of ethyl acetate. The organic layer was washed with 0.1 N sodium thiosulfate aqueous solution and saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (methylene chloride-acetone) to give 2.35 g of [N-(4-iodomethyloxycarbonylbutanoyl)-glycyl]-L-proline P-nitrobenzyl ester [Compound (24)] as yellowish oil. 1 H-NMR (CDCl 3 ) δ : 1.92∼2.17 (m, 5H), 2.17∼2.37 (m, 1H), 2.33 (t, 2H, J = 7.3Hz), 2.42 (t, 2H, J = 7.3Hz), 3.46∼3.74 (m, 2H), 4.02 (dd, 1H, J = 4.0Hz, 17.8Hz), 4.12 (dd, 1H, J = 4.3Hz, 17.8Hz), 4.59 (dd, 1H, J = 4.0Hz, 8.9Hz), 5.24 (d, 1H, J = 13.5Hz), 5.32 (d, 1H, J = 13.5Hz), 5.91 (s, 2H), 6.45 (br, 1H), 7.53 (d, 2H, J = 8.9Hz), 8.24 (d, 2H, J = 8.9Hz) Example 1: 770 mg of 28 % sodium methoxide-methanol solution was added to a mixture solution of 862 mg of Compound (4) obtained in the step (c) of Preparation 1 in 20 ml of anhydrous methanol under ice-cooling and nitrogen gas stream. Then the reaction mixture was stirred for 10 minutes under the same conditions. After reaction, 4 ml of 2N-HCl was added to the reaction mixture and the solvent was removed under reduced pressure to give the crude Compound (25). Then, the crude Compound (25) was dissolved in the mixture solution of anhydrous acetonchloroform and to this solution were dded 2430 mg of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate [Compound (26)] and 2.8 ml of diisopropylethylamine under ice-cooling and nitrogen gas stream. After stirring the reaction mixture for 2 hours under the same conditions, ethyl acetate was added and the separated organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated saline solution. The solvent was removed and the resulting residue was purified by silica gel column chromatography with chloroform : aceton (1 : 2) to give 1339 mg (65 % from Compound (4)) of p-nitrobenzyl (1R,5S,6S)-2-[1-(thiazolin-2-yl)azetidin-3-yl]-thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate [Compound (27)]. 1 H-NMR (CDCl 3 ) δ : 1.235 (d, 3 H, J = 7.26Hz), 1.349 (d, 3H, J = 6.27Hz), 3.160 (quintet, 1H, J = 7.26 Hz), 3.265 (dd, 1H, J = 2.3, 6.26Hz), 3.367 (t, 2 H, J = 7.26Hz), 3.898∼4.038 (m, 4H), 4.071∼4.147 (m, 1H), 4.212∼4.278 (m, 2H), 4.372 (2H, J = 7.92 Hz), 5.255 5.517 (d (AB), 2H, J = 13.85 Hz), 7.665 (d, 2H, J = 8.58 Hz), 8.226 (d, 2H, J = 8.58Hz) Example 2: To a mixture solution of 1339 mg of Compound (27) obtained in Example 1 in 2 ml of tetrahydrofuran were added 60 ml of 0.38 M phosphate buffer solution and 11.2 g of zinc powder, and the reaction mixture was vigorously stirred for 2 hours. After the reaction, unsolved substance was removed by using Celite® and the filtrate was washed with ethylacetate and the pH of the filtrate was adjusted to 5.5. Then, the filtrate was concentrated and the resulting residue was purified by using Diaion HP-40R column (5 % isopropylalcohol-water) to give 630 mg (64 %) of (1R,5S,6S)-2-[1-(thiazolin-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid [Compound (28)]. 1 H-NMR (D 2 O) δ : 1.093 (d, 3H, J = 6.93Hz), 1.207 (d, 3H, J = 6.27 Hz), 3.05∼3.20 (m, 1H), 3.357 (dd, 1H, J = 2.3, 5.94Hz), 3.558 (t, 2H, J = 7.26 Hz), 3.920 (t, 2H, J = 7.26 Hz), 4.00∼4.20 (m, 5H), 4.20∼4.30 (m, 1H), 4.60∼4.70 (m, 1H) IR(KBr) : 1740, 1640, 1590cm -1 Example 3: To a solution of 600 mg of Compound (9) obtained in the step (d) in Preparation 2 in 10 ml of anhydrous methanol was added 400 mg of 28 % sodium methoxide-methanol solution under ice-cooling and nitrogen atmosphere, and the reaction mixture was stirred for 5 minutes under the same conditions. After the reaction, 0.355 ml of acetic acid was added and the solvent was removed under reduced pressure. The resulting residue was dissolved in 5 m of anhydrous acetonitrile and the unsolved substance was removed by filtration. Then, this filtrate was added to a solution of 1.230 g of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate [Compound (26)] in 5 ml of anhydrous acetonitrile under ice-cooling, and 2.2 ml of diisopropylethylamine was further added dropwise to the reaction mixture. After stirring the reaction mixture for 1.5 hour under the same condition. The solvent was removed under reduced pressure. The resulting residue was dissolved in ethyl acetate and the organic layer was washed with saturated sodium bicarbonate aqueous solution, and dried over magnesium sulfate. After removal of the solvent, the resulting residue was purified by silica gel column chromatography (chloroform-acetone) to give 0.788 g (64 % from Compound (26)) of p-nitrobenzyl (1R,5S,6S)-2-[1-(4(R)-methoxymethyloxymethyl-1,3-thiazolin-2-yl)-azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate [Compound (30)]. 1 H-NMR (CDCl 3 ) δ : 1.24 (d, 3H, J = 7.3Hz), 1.36 (d, 3H, J = 6.3Hz), 3.16 (dq, 1H, J = 7.3, 9.2Hz), 3.25-3.34 (m, 2H), 3.37 (m, 2H), 3.43-3.47 (m, 1H), 3.51 (dd, 1H, J = 7.9, 9.9Hz), 3.67 (dd, 1H, J = 5.0, 9.9Hz), 2.94-4.00 (m, 2H), 4.07-4.17 (m, 1H), 4.23 (dd, 1H, J = 2. 6, 9.2Hz), 4.20-4.30 (m, 1H), 4.30-4.51 (m, 3H), 4.66 (s, 2H), 5.25 (d, 1H, J = 13.9Hz), 5.51 (d, 1H, J = 13.9Hz), 7.66 (d, 2H, J = 8.6H z), 8.23 (d, 2H, J = 8.6Hz) Example 4: To a solution of 756 mg of Compound (30) obtained in Example 3 in 10 ml of tetrahydrofuran and 30 ml of 0.35 M phosphate buffer (pH 6.0) solution was added 6.0 g of zinc powder, and the reaction mixture was stirred for 2 hours at room temperature. After removal of the zinc powder by filtration, the filtrate was washed with ethyl acetate and the pH of the filtrate was adjusted to 5.5, then the filtrate was concentrated. The resulting residue was purified by using Diaion HP-40R column (10 % isopropanol-water) to give 415 mg (71 %) of (1R,5S,6S)-2-[1-((4R)-methoxymethyloxymethyl-1,3-thiazolin-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylic acid [Compound (31)]. 1 H-NMR (D 2 O) δ : 1.10 (d, 3H, J = 7.3Hz), 1.21 (d, 3H, J = 6.6Hz), 3.06-3.18 (m, 1H), 3.22-3.33 (m, 1H), 3.33 (s, 3H), 3.36-3.47 (m, 1H), 3.61-3.75 (m, 3H), 4.09-4.31 (m, 6H), 4.33-4.56 (m, 1H), 4.60-4.68 (m, 3H) IR (KBr) : 1735, 1640, 1580cm -1 Example 5: A mixture solution of 430 mg (1.12 mM) of Compound (28) obtained in the Example 2 and 94.1 mg (1.12 mM) of sodium bicarbonate in 15 ml of water was lyophilized. The resulting amorphous solid was dissolved in 5 ml of dimethylformamide, and 285 mg (1.18 mM) of pivalic acid iodomethyl ester was added to this solution and the reaction mixture was stirred for 1 hour at room temperature. After reaction, ethyl acetate was added to the reaction mixture and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saline, and dried over magnesium sulfate. After removal of the solvent, the resulting residue was purified by silica gel column chromatography (10 % methanol-chloroform) to give 415 mg of (74.6 %) of pivaloyloxymethyl (1R,5S,6S)-2-[1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate [Compound (32)]. 1 H-NMR (CDCl 3 ) δ : 1.229 (s, 9H), 1.229 (d, 3H, J = 7.3Hz), 1.339 (d, 3H , 6.3Hz), 3.165 (dd, 1H, J = 7.3Hz, 9.2Hz), 3.227 (dd, 1H, J = 2.6Hz, 6.9Hz), 3.369 (t, 2H, 7.3Hz), 3.952 (dd, 2H, 5 6Hz, 8.6Hz), 3.988∼4.043 (m, 2H), 4.085∼4.162 (m, 1H), 4.183∼4.274 (m, 2H), 4.346∼4.426 (m, 2H), 5.842 (d, 1H, J = 5.6Hz), 5.972 (d, 1H, J = 5.6Hz) Example 6: A mixture solution of 500 mg (1.30 mM) of Compound (28) obtained in the Example 2 and 109.4 mg (1.30 mM) of sodium bicarbonate in 15 ml of water was lyophilized. The resulting amorphous solid was dissolved in 5 ml of dimethylformamide, and 379.5 mg (1.30 mM) of 1-iodoethylcyclohexylcarbonate [prepared by the method discribed in The Journal of Antibiotics, vol. XL, No. 1, page 81] was added to this solution, and the reaction mixture was stirred for 2 hours at room temperature. After reaction, ethyl acetate was added to the reaction mixture and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (10 % methanolchloroform) to give 309 mg of (43 %) of 1-[(cyclohexyloxy)carbonyloxy] ethyl (1R,5S,6S)-2-[1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate [Compound (33)]. 1 H-NMR (CDCl 3 ) δ : 1.219 (d, 3H, J = 7.3Hz), 1.323 (d, 3H, J = 6.3Hz), 1.37∼1.50 (m, 2H), 1.563 (d, 1.5H, J = 5.3Hz), 1.611 (d, 1.5H, J = 5.3Hz), 1.67∼1.82 (m, 4H), 1.90∼2.05 (m, 4H), 3.20 (m, 1H), 3.216 (dd, 1H, J = 2.7Hz, 6.9Hz), 3.367 (t, 2H, J = 7.6Hz), 3.92∼4.04 (m, 4H), 4.08∼4.25 (m, 3H), 4.34∼4.43 (m, 2H), 4.59∼4.71 (m, 1H), 6.880 (q, 0.5H , J = 5.3Hz), 6.890 (q, 0.5H, J = 5.3Hz) Example 7: Other ester compounds of (1R,5S,6S)-2-[1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylic acid represented by the above formula were obtained by reacting Compound (28) with Compound (18) [obtained in the Preparation 4], Compound (20) [obtained in the Preparation 5] and Compound (24) [obtained in the Preparation 6] respectively. Example 8: Compound (34) was obtained in substantially the same manner as that of Examples 1 and 2. 1 H-NMR (D 2 O) δ : 1.16 (d, 3H, J=6.9Hz), 1.27 (d, 3H, J=6.3 Hz), 2.95 (s, 3H) , 3.11 (s, 3H), 3.19 (m, 1H), 3.41 (dd, 1H, J=2.5Hz, 6.1Hz) , 3.57 (dd, 1H, J=5.9Hz, 11.5Hz) , 3.89 (dd, 1H, J = 8.6Hz, 11.5Hz) , 4.11∼4.37 (m, 5H), 4.62∼4.80 (m, 2H), 5.37 (dd, 1H, J=5.9Hz, 8.6Hz)

Claims: 3-Mercapto-1-(1,3-thiazolin-2-yl)azetidine derivatives represented by formula (IX) below or acid addition salts thereof wherein R is hydrogen; C 1 -C 7 alkyl group which is unsubstituted or substituted by hydroxy, C 1 -C 7 alkoxy or C 1 -C 7 alkoxy-C 1 -C 7 alkoxy group; group -COOR 1 (R 1 is hydrogen or C 1 -C 7 alkyl group) ; or group -CONR 2 R 3 (R 2 and R 3 areindependently each other, hydrogen or C 1 -C 7 alkyl). The compound of claim 1 which is 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine of the following formula: or acid addition salt thereof. The compound of claim 1 which is 3-mercapto-1-(4-methoxymethoxymethyl-1,3-thiazolin-2-yl)azetidine of the following formula: or acid addition salt thereof. A process for manufacturing the compound represented by formula (IX) of claim 1 or an acid addition salt thereof, which process is characterized in that the acetyl group is cleaved off from 3-acetylthio-1-(1,3-thiazolin-2-yl)azetidine derivative represented by formula (XIII) below or an acid addition salt thereof wherein R has the same meaning as defined in claim 1. The process of claim 4 wherein R is hydrogen. The process of claim 4 wherein R is methoxymethoxymethyl. A process for manufacturing the compound represented by formula (IX) of claim 1 or an acid addition salt thereof, which process is characterized in that (a) 3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine derivative represented by formula (XIV) below wherein R has the same meaning as defined in claim 1 is made to react with di(lower)alkylazodicaroboxylate, triphenylphosphine and thioacetic acid, and that (b) the acetyl group is cleaved off from the resulting 3-acetylthio-1-(1,3-thiazolin-2-yl)azetidine derivative represented by formula (XIII) below or an acid addition salt thereof wherein R has the same meaning as defined in claim 1. The process of claim 7 wherein R is hydrogen. The process of claim 7 wherein R is methoxymethoxymethyl. 3-Acetylthio-1-(1,3-thiazolin-2-yl)azetidine derivative represented by formula (XIII) below or an acid addition salt thereof wherein R has the same meaning as defined in claim 1. The compound of claim 10 which is 3-acetylthio-1-(1,3-thiazolin-2-yl)azetidine of the following formula or an acid addition salt thereof. The compound of claim 10 which is 3-acetylthio-1-(4-methoxymethoxymethyl-1,3-thiazolin-2-yl)azetidine of the following formula: or an acid addition salt thereof. 3-Hydroxy-1-(1,3-thiazolin-2-yl)azetidine derivative represented by formula (XIV) below or an acid addition salt thereof wherein R has the same meaning as defined in claim 1. The compound of claim 13 which is 3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine of the following formula or an acid addition salt thereof. The compound of claim 10 which is 3-hydroxy-1-(4-methoxymethoxymethyl-1,3-thiazolin-2-yl)azetidine of the following formula: or an acid addition salt thereof. A process for manufacturing the compound represented by formula (XIV) of claim 13 or an acid addition salt thereof, which process is characterized in that 3-hydroxyazetidine represented by formula (XV) below is made to react with 2-methylthio-1,3-thiazolidine derivative by formula (XVI) below wherein R has the same meaning as defined in claim 1. The process of claim 7 wherein R is hydrogen. The process of claim 7 wherein R is methoxymethoxymethyl.

Inventors: ABE TAKAO, ISODA TAKESHI, KUMAGAI TOSHIO, MIHIRA ADO, SATO CHISATO, TAMAI SATOSHI, ABE, TAKAO, ISODA, TAKESHI, KUMAGAI, TOSHIO, MIHIRA, ADO, SATO, CHISATO, TAMAI, SATOSHI
Applicants: WYETH K K, WYETH K.K.
Application year: 1994
Main classification: C07D417
IPC codes: C07D417, C07D477